Improved functional outcome after chronic stroke with delayed anti-Nogo-A therapy: A clinically relevant
Katherine M Podraza1,2, Yasmin Mehta1, Vicki A Husak1
11 Research Service, Edward Hines Jr. Veterans Affairs Hospital, Hines, IL, USA.
Abstract:
Many preclinical treatment strategies for stroke have failed when tested in human trials. Although the reasons for these translation failures are multifactorial, one potential concern is the statistical analysis of the preclinical data. One way to rigorously evaluate new therapies is to use an intention-to-treat analysis in preclinical studies. Therefore, in this study, we set out to evaluate the treatment efficacy of a potential clinically relevant therapeutic agent for stroke, i.e., anti-Nogo-A immunotherapy, using an intention-to-treat analysis. Adult rats were trained on the skilled forelimb reaching task and subsequently underwent an ischemic stroke. Nine weeks later, the rats either received intracerebroventricular anti-Nogo-A antibody, control antibody, or no treatment. Skilled reaching performance was assessed by a non-linear model using both an intention-to-treat and per-protocol analysis. Following testing, dendritic complexity was evaluated in the contralesional and perilesional sensorimotor cortex. Both intention-to-treat and per-protocol analysis showed that anti-Nogo-A immunotherapy resulted in statistically significant improved recovery on the skilled forelimb reaching task, although treatment effect was less (though statistically significant) in the intention-to-treat group. Improved functional performance was not shown to be associated with dendritic changes. In conclusion, this study provides evidence for the importance of using intention-to-treat paradigms in testing preclinical therapeutic strategies.
Insights
Intention-to-treat analysis in preclinical stroke studies, using anti-Nogo-A immunotherapy, showed significant functional recovery. This rigorous statistical approach is crucial for evaluating stroke therapies effectively.
Area of Science:
- Neuroscience
- Translational Medicine
- Biostatistics
Background:
- Preclinical stroke treatment strategies often fail in human clinical trials.
- Statistical analysis methods in preclinical research may contribute to translation failures.
- Intention-to-treat (ITT) analysis is a rigorous method for evaluating treatment efficacy.
Purpose of the Study:
- To evaluate the efficacy of anti-Nogo-A immunotherapy for stroke using an intention-to-treat analysis.
- To compare intention-to-treat analysis with per-protocol analysis in a preclinical stroke model.
Main Methods:
- Adult rats with ischemic stroke were treated with anti-Nogo-A antibody or control.
- Skilled forelimb reaching performance was assessed using a non-linear model.
- Intention-to-treat and per-protocol analyses were performed.
- Dendritic complexity was evaluated post-testing.
Main Results:
- Both ITT and per-protocol analyses demonstrated statistically significant improvement in skilled reaching recovery with anti-Nogo-A immunotherapy.
- The treatment effect size was smaller, though still significant, in the ITT group compared to the per-protocol group.
- No association was found between improved functional performance and changes in dendritic complexity.
Conclusions:
- Intention-to-treat analysis provides a more rigorous evaluation of preclinical stroke therapies.
- Anti-Nogo-A immunotherapy shows potential for stroke recovery.
- The study highlights the importance of appropriate statistical paradigms in preclinical research for successful translation.
